Method and Composition for Treating Seizure Disorders

ABSTRACT

A composition for treating seizure disorders such as epilepsy comprises (i) an anticonvulsant drug of the hydantoin family; (ii) phytocannabinoid cannabidiol (CBD); and (iii) a fat-soluble vitamin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 16/308,837, filed Dec. 11, 2018; which is the national stage of International Application No. PCT/US2017/037394, filed Jun. 14, 2017; which claims priority from U.S. Provisional Application No. 62/350,215, filed Jun. 15, 2016; each of which is hereby incorporated by reference herein in its entirety.

FIELD AND BACKGROUND OF THE INVENTION

This invention relates to compositions and methods for treating multiple types of seizure disorders and epilepsy in humans and animals (mammals) using a combination of phytocannabinoid cannabidiol (CBD), a hydantoin anticonvulsant drug and a P450 blocking compound such as vitamins A, D, E and K.

About 50 million people worldwide are affected by epilepsy (Sander, 2003). Epilepsy is due to multiple factors including sodium, potassium, GABA and NMDA. Modulating one or more of these receptors is required to maximally control epilepsy. It is believed that monotherapy is adequate in up to 25 percent of patients.

The use of CBD in combination with standard anti-epileptic drug (SAED) that acts via sodium or calcium channels for the treatment of epilepsy is described in US 2013/0296398 A1.

Several researchers have suggested that cannabis-based medicines may have the potential to treat hyperexcitability in the central nervous system (Wingerchuk, 2004; Alger, 2006)

Consroe et al. in 1975 described the case of a young man for whom the standard treatment of phenobarbital and phenytoin did not control his seizures. When the young man smoked cannabis, he had no seizures. They concluded that cannabis might have anticonvulsant effects on human epilepsy.

In 1990, a study by Ng involving a population of 308 epileptic patients showed that the use of cannabis reduced seizures. However, the study was later criticized in a report from the Institute of Medicine (1999) that claimed health status prior to hospital admissions may have been a factor that influenced their drug use rather than the other way around.

In 1980, Cunha et al. reported that patients that were administered 200-300 mg of cannabidiol in combination with regular medication showed improvement over those that received a placebo. Mild sedation was reported as an unwanted side effect.

In 1986, Ames reported a study in which 12 epileptic patients were given 200-300 mg of cannabidiol per day in combination with standard antiepileptic drugs with no significant improvement in seizure frequency.

In 1990, Trembly et al. reported that 900-1200 mg of cannabidiol a day for 10 months markedly reduced the frequency of seizures in the single patient that they tested.

In addition to reports that suggest that CBD may be beneficial, a report by Davis and Ramsey shows that use of tetrahydrocannabinol (THC) may also help reduce seizures.

Cannabis has been shown to be both pro-convulsant (Brust et al., 1992) and anti-convulsant. This study shows that it is not clear if the use of cannabis is a potential risk factor to recreational and medicinal users (Ferdinand et al., 2005).

WO02/064109 describes a pharmaceutical formulation where the cannabinoids THC and CBD are used.

GB091158.9 describes the use of THCV for the treatment of generalized seizures.

The onset of epileptic seizures can be life threatening including long-term implications (Lutz, 2004) including mental health problems, cognitive deficits and morphological changes (Swann, 2004; Avoli et al., 2005). The onset of epilepsy also greatly affects lifestyle as suffers live in the fear of consequential injury or the inability to perform daily tasks (Fisher et al., 2000).

The present invention identifies a novel drug combination that will enhance or otherwise offer benefits in the use of certain SAEDs.

SUMMARY OF THE INVENTION

The invention provides a composition for treating seizure disorders such as epilepsy comprising: (i) an anticonvulsant drug of the hydantoin family such as phenytoin; (ii) phytocannabinoid cannabidiol (CBD); and (iii) a fat-soluble vitamin such as vitamin A. The composition can also include a water-soluble vitamin such as folic acid to reduce side effects and boost metabolism.

The invention also provides a composition for decreasing the metabolic side effects of CBD and increasing its bioavailability to a patient by combining CBD and a fat-soluble vitamin like vitamin A in an amount that produces the desired effect.

The invention also provides a method for treating seizure disorders in mammals such as epilepsy by administering to a subject in need thereof a composition including: (i) an effective amount of an anticonvulsant drug of the hydantoin family; (ii) phytocannabinoid cannabidiol (CBD) in a dosage amount sufficient to inhibit degradation of said anticonvulsant drug; and (iii) a fat-soluble vitamin in an amount effective to inhibit degradation of said anticonvulsant drug and CBD thereby increasing the amount of bioavailable anticonvulsant drug and CBD to said patient. A water-soluble vitamin like folic acid can be administered separately to reduce side effects or it can be included in the composition.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT(S) OF THE INVENTION

Hydantoin drugs such as Dilantin induce the cytochrome P450 hepatic enzyme system. It is believed that this is responsible for the degradation and/or metabolism of CBD and the first pass metabolism of Dilantin. Using a higher dose of CBD in combination with a fat-soluble vitamin like vitamin A is believed to overcome the metabolic effect of cytochrome P450 enzyme and increase the bioavailability of Dilantin and CBD. The combination of CBD and vitamin A in combination with a lower dose of standard Dilantin to relieve multiple types of seizure disorder and epilepsy and obtain the desired cumulative anticonvulsant effect and reduced side effects of Dilantin could not be anticipated.

Anticonvulsant hydantoins that can be used in the invention are selected from the group of ethotoin, fosphenytoin, mephenytoin and phenytoin. Each is available commercially under various brand names: Dilantin and Epanutin (phenytoin); Peganone (ethotoin); Mesantoin (mephenytoin); and Cerebyx (fosphenytoin).

Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. This blocks sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state.

Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissociate from the inactive channel, there is a time dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.

The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyper excitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses, which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.

Other hydantoins used in the invention have similar mechanisms of action.

Cuttle et al. (Drug Metab. Dispos. 2000 August; 28(8): 945-50) have reported that phenytoin provokes a skin rash in 5 to 10% of patients receiving the drug for the treatment of seizures and other disorders. Cytochrome P450 enzymes metabolize phenytoin. Reactive drug metabolites are believed to cause covalent modification of normal self proteins by which can bring about a skin rash. Patients treated according to the invention with reduced amounts of hydantoin drug will experience fewer incidents of skin rash.

CBD can be used in its pure form or as a mixture of compounds that result from extracting cannabis plants. Such mixtures contain CBD, THC or tetrahydrocannabinol (which in turn is a mixture comprising 9-tetrahydrocannabinol (delta-9 THC), 8-tetrahydrocannabinol (delta-8 THC) and 9-THC Acid), Cannabinol (CBN), Cannabichromene (CBC), Cannabigerol (CBG), terpenoids and flavonoids.

The preferred CBD mixture is extracted from a Cannabis indica, the composition of which is known. The use of CBD from Cannabis indica, which can contain up to 50% THC (based on the amount of CBD), is preferred. See, for example, Qureshi et al., World Applied Sciences Journal 19(7): 918-923, 2012 ISSN 1818-4952, IDOSI Publications, 2012, disclosing a Cannabis indica extract containing 54% CBD and 24% THC. Preferred mixtures for use in the invention contain at least 50% by weight CBD wherein the weight ratio of CBD to THC is at least 2:1, preferably at least 3:1.

The preferred CBD mixture is extracted from a Cannabis indica dominant strain, or a hybrid Cannabis indica/Cannabis sativa strain, using high pressure and carbon dioxide as a solvent in a 1500-20 L subcritical/supercritical CO2 system using a Super Critical Systems, for example made by Apeks, 14381 Blamer Rd., Johnstown, Ohio, 43031. See http://www.apekssupercritical.com/botanical-extraction-systems/.

Apeks Systems, as an example, use valve less expansion technology with no constrictions or regulating valves to cause clogging in the system between the extraction vessel and the CO2 expansion separator. Flow of liquid CO2 and dissolved oil travels from the extraction vessel into the separator, and the oil is separated from the CO2 in the separator/collection vessel. CO2 is recycled during the extraction process and recovered; regenerative heat capture methods are used to increase efficiency.

A further process using solvents can be used to remove THC from the mixture leaving either pure CBD or so-called “organic CBD” containing CBD, CBN, CBC, CBG CBN, terpenoids and flavonoids. The use of essentially THC-free Organic CBD from Cannabis indica is more preferred.

Another source of CBD essentially free of THC is the CBD mixture obtained from hemp or by extracting hempseed oil. See Leizer et al., J. Nutraceuticals, Functional and Medical Foods, Vol. 2(4) 2000, The Haworth Press, Inc. Elixinol (D&G Health LLC) is a predominantly CBD product extracted from hempseed oil that contains trace amounts of THC.

The preferred blocking compound is a natural or synthetic fat-soluble vitamin normally stored in fatty tissue such as vitamins A, D, E and K.

Vitamin A is a fat-soluble group of unsaturated compounds that includes retinol, retinal, retinoid acid, beta-carotene and other provitamin A carotenoids. Vitamin A is preferred because it is less likely to interact with other medications.

Vitamin D is a fat-soluble secosteroid such as cholecalciferol and ergocalciferol.

Vitamin E is commonly gamma-tocopherol from corn or soybean oil, or alpha-tocopherol from wheat germ oil or sunflower and safflower oils.

Vitamin K is synthesized by plants and is a family 2-methyl-1,4-naphthoquinone (3-) derivatives.

Natural or synthetic water-soluble vitamins can be used to reduce side effects and boost the immune system and include folic acid, folate, vitamin B9 and vitamin B12.

The preferred water-soluble vitamin is folic acid, which is the synthetic form of vitamin B also known as pteroylglutamic acid.

Patients who are subject to seizure disorders such as epilepsy, and skin rashes, are treated to control and reduce the frequency of seizures and skin rashes by administering the drug combination described above in accordance with further details of the invention, which are disclosed herein.

Patients being treated for seizure disorders usually receive an anticonvulsant drug such as phenytoin in amounts of about 10 to as much as 20 mg/kg of patient weight per day. Because of the P450 blocking effect provided by a fat-soluble vitamin, the bioavailability of hydantoin drugs and CBD is increased which allows the use of lesser amounts of a hydantoin drug with a concomitant lowering in undesirable side effects normally seen with drugs like phenytoin, especially fewer skin rashes. Thus, it is preferred to use hydantoin dosages of about 30% less that the normal dosage when the drug is given alone, or from about 7 to about 14 mg/kg of patient body weight, and more preferably not more than about 7 mg/kg of patient body weight per day.

The dosage amount of CBD to be used with the anticonvulsant drug is from about 0.5 to about 1.0 mg/kg of patient weight.

Another embodiment of this invention is a composition for decreasing the metabolic side effects of CBD and increasing its bioavailability to a patient by combining CBD and a fat-soluble vitamin like vitamin A in an amount that produces the desired effect, for example from about 0.5 to about 1.0 mg/kg patient body weight. In this embodiment, it is expected that the therapeutic dosage of CBD can be reduced by 10 to 30%.

The dosage of fat-soluble vitamin, especially vitamin A, is about 100 IU to about 2000 IU per kg of patient body weight per day.

A water-soluble vitamin, especially folic acid, can be administered separately at from about 1 to about 20 mg/day or compounded with the other components in a dosage amount of about 0.5 to about 1.0 mg/kg of patient weight.

Candidates to be treated according to the invention will generally present with symptoms or signs associated with seizure disorders such as recurrent loss of consciousness, recurrent seizures and/or a prior diagnosis of medically refractory epilepsy. The invention is especially useful in treating patients who have had recurrent and/or poorly controlled seizures or epilepsy in spite of being treated with one or more know anticonvulsant drugs.

The expected response in patients treated according to the invention is a reduction in seizure intensity and/or frequency once a steady state of the active pharmaceutical components is achieved. Up to 14 or more days of treatment may be required before benefits are achieved. The same applies to patients experiencing skin rashes from taking hydantoin to control seizures.

Patients with allergies, cardiac rhythm disturbances, metabolic syndrome or a history of Cannabis abuse are not candidates to be treated according to the invention.

Animals, especially dogs and cats, can be treated according to the invention. Seizures in dogs and cats are caused by abnormal brain activity; they can to subtle or cause violent convulsions. Some seizures only occur once but repeated seizures require treatment to prevent larger areas of the brain from becoming affected. Dosage amounts and serum levels of drug are the same as disclosed above for human patients.

While this invention has been described as having preferred sequences, ranges, ratios, steps, order of steps, materials, structures, symbols, indicia, graphics, color scheme(s), shapes, configurations, features, components, or designs, it is understood that it is capable of further modifications, uses and/or adaptations of the invention following in general the principle of the invention, and including such departures from the present disclosure as those come within the known or customary practice in the art to which the invention pertains, and as may be applied to the central features hereinbefore set forth, and fall within the scope of the invention and of the limits of the claims appended hereto or presented later. The invention, therefore, is not limited to the preferred embodiment(s) shown/described herein. 

1. Method for treating a patient having a seizure disorder, which is effective to reduce seizure intensity and/or seizure frequency, comprising administering daily to the patient at least (i) an anticonvulsant drug of the hydatoin family in an amount of not greater than about 7 mg/kg of the patient's body weight, (ii) cannabidiol (CBD) in an amount sufficient to inhibit degradation of the anticonvulsant drug by a cytochrome P450 enzyme such that bioavailability of the anticonvulsant drug is increased, (iii) a water-soluble vitamin, and (iv) a fat-soluble vitamin.
 2. Method of claim 1 wherein the anticonvulsant drug is selected from the group consisting of ethotoin, fosphenytoin, mephenytoin and phenytoin.
 3. Method of claim 1 wherein the CBD is extracted from Cannabis indica or Cannabis sativa or a hybrid of Cannabis indica and Cannabis sativa.
 4. Method of claim 1 wherein the CBD is organic CBD.
 5. Method of claim 1 wherein the CBD is pure or synthetic CBD.
 6. Method of claim 1 wherein the CBD is obtained from hemp or by extracting hempseed oil.
 7. Method of claim 1 wherein the CBD is in an amount of from about 0.5 to about 1.0 mg/kg of the patient's body weight.
 8. Method of claim 1 wherein the water-soluble vitamin is selected from the group consisting of folic acid, folate, vitamin B9 and vitamin B12.
 9. Method of claim 8 wherein the water-soluble vitamin is folic acid.
 10. Method of claim 1 wherein the water-soluble vitamin is in an amount of from about 0.5 to about 1.0 mg/kg of the patient's body weight.
 11. Method of claim 1 wherein the fat-soluble vitamin is selected from the group consisting of vitamins A, D, E and K.
 12. Method of claim 11 wherein the fat-soluble vitamin is vitamin A.
 13. Method of claim 1 wherein the fat-soluble vitamin is in an amount of about 100-2000 IU/kg of the patient's body weight.
 14. Method of claim 1 wherein the anticonvulsant drug is in an amount of not greater than about 2 mg/kg of the patient's body weight.
 15. Method of claim 1 wherein the seizure disorder is epilepsy.
 16. Method for treating a patient having a seizure disorder, which is effective to reduce seizure intensity and/or seizure frequency, comprising administering daily to the patient at least (i) an anticonvulsant drug of the hydatoin family in an amount of not greater than about 7 mg/kg of the patient's body weight, (ii) cannabidiol (CBD) in an amount sufficient to inhibit degradation of the anticonvulsant drug by a cytochrome P450 enzyme such that bioavailability of the anticonvulsant drug is increased, (iii) a water-soluble vitamin in an amount of from about 0.5 to about 1.0 mg/kg of the patient's body weight, and (iv) a fat-soluble vitamin in an amount of at least about 100-2000 IU/kg of the patient's body weight.
 17. Method of claim 16 wherein the anticonvulsant drug is in an amount of not greater than about 2 mg/kg of the patient's body weight.
 18. Method of claim 17 wherein the seizure disorder is epilepsy.
 19. Method for treating a patient having a seizure disorder, which is effective to reduce seizure intensity and/or seizure frequency, comprising (a) administering daily to the patient at least (i) an anticonvulsant drug of the hydatoin family in an amount of not greater than about 7 mg/kg of the patient's body weight, (ii) CBD in an amount of from about 0.5 to about 1.0 mg/kg of the patient's body weight, and (iii) a fat-soluble vitamin in an amount of about 100-2000 IU/kg of the patient's body weight; (b) separately administering to the patient at least a water-soluble vitamin in an amount of about 1-20 mg/day.
 20. Method of claim 19 wherein the anticonvulsant drug is in an amount of not greater than about 2 mg/kg of the patient's body weight. 